Dynamic profiling of medulloblastoma surfaceome
Abstract Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the fo...
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| Format: | Article |
| Language: | English |
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BMC
2023-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01609-7 |
| _version_ | 1797451116651216896 |
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| author | David Bakhshinyan Yujin Suk Laura Kuhlmann Ashley A. Adile Vladimir Ignatchenko Stefan Custers William D. Gwynne Andrew Macklin Chitra Venugopal Thomas Kislinger Sheila K. Singh |
| author_facet | David Bakhshinyan Yujin Suk Laura Kuhlmann Ashley A. Adile Vladimir Ignatchenko Stefan Custers William D. Gwynne Andrew Macklin Chitra Venugopal Thomas Kislinger Sheila K. Singh |
| author_sort | David Bakhshinyan |
| collection | DOAJ |
| description | Abstract Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin 𝛼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB. |
| first_indexed | 2024-03-09T14:50:15Z |
| format | Article |
| id | doaj.art-4d03f9f8846c4b28a993fd246a4af2b1 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-09T14:50:15Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-4d03f9f8846c4b28a993fd246a4af2b12023-11-26T14:31:47ZengBMCActa Neuropathologica Communications2051-59602023-07-0111111410.1186/s40478-023-01609-7Dynamic profiling of medulloblastoma surfaceomeDavid Bakhshinyan0Yujin Suk1Laura Kuhlmann2Ashley A. Adile3Vladimir Ignatchenko4Stefan Custers5William D. Gwynne6Andrew Macklin7Chitra Venugopal8Thomas Kislinger9Sheila K. Singh10McMaster Centre for Discovery in Cancer Research, McMaster UniversityMcMaster Centre for Discovery in Cancer Research, McMaster UniversityPrincess Margaret Cancer Center, UHNMcMaster Centre for Discovery in Cancer Research, McMaster UniversityPrincess Margaret Cancer Center, UHNMcMaster Centre for Discovery in Cancer Research, McMaster UniversityMcMaster Centre for Discovery in Cancer Research, McMaster UniversityPrincess Margaret Cancer Center, UHNMcMaster Centre for Discovery in Cancer Research, McMaster UniversityPrincess Margaret Cancer Center, UHNMcMaster Centre for Discovery in Cancer Research, McMaster UniversityAbstract Medulloblastoma (MB) is the most common type of malignant pediatric brain cancer. The current standard of care (SOC) involves maximal safe resection and chemoradiotherapy in individuals older than 3 years, often leading to devastating neurocognitive and developmental deficits. Out of the four distinct molecular subgroups, Group 3 and 4 have the poorest patient outcomes due to the aggressive nature of the tumor and propensity to metastasize and recur post therapy. The toxicity of the SOC and lack of response in specific subtypes to the SOC underscores the urgent need for developing and translating novel treatment options including immunotherapies. To identify differentially enriched surface proteins that could be evaluated for potential future immunotherapeutic interventions, we leveraged N-glycocapture surfaceome profiling on Group 3 MB cells from primary tumor, through therapy, to recurrence using our established therapy-adapted patient derived xenograft model. Integrin 𝛼5 (ITGA5) was one of the most differentially enriched targets found at recurrence when compared to engraftment and untreated timepoints. In addition to being enriched at recurrence, shRNA-mediated knockdown and small molecule inhibition of ITGA5 have resulted in marked decrease in proliferation and self-renewal in vitro and demonstrated a survival advantage in vivo. Together, our data highlights the value of dynamic profiling of cells as they evolve through therapy and the identification of ITGA5 as a promising therapeutic target for recurrent Group 3 MB.https://doi.org/10.1186/s40478-023-01609-7MedulloblastomaProteomicsIntegrins |
| spellingShingle | David Bakhshinyan Yujin Suk Laura Kuhlmann Ashley A. Adile Vladimir Ignatchenko Stefan Custers William D. Gwynne Andrew Macklin Chitra Venugopal Thomas Kislinger Sheila K. Singh Dynamic profiling of medulloblastoma surfaceome Acta Neuropathologica Communications Medulloblastoma Proteomics Integrins |
| title | Dynamic profiling of medulloblastoma surfaceome |
| title_full | Dynamic profiling of medulloblastoma surfaceome |
| title_fullStr | Dynamic profiling of medulloblastoma surfaceome |
| title_full_unstemmed | Dynamic profiling of medulloblastoma surfaceome |
| title_short | Dynamic profiling of medulloblastoma surfaceome |
| title_sort | dynamic profiling of medulloblastoma surfaceome |
| topic | Medulloblastoma Proteomics Integrins |
| url | https://doi.org/10.1186/s40478-023-01609-7 |
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